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Category: genetics – Page 4

Reversing aging in blood stem cells by targeting lysosomal dysfunction

As people age, these cells become defective and lose their ability to renew and repair the blood system, decreasing the body’s ability to fight infections as seen in older adults. Another example is a condition called clonal hematopoiesis; this asymptomatic condition is considered a premalignant state that increases the risk of developing blood cancers and other inflammatory disorders. Its prevalence increases significantly with age.

The team discovered that lysosomes in aged HSCs become hyper-acidic, depleted, damaged, and abnormally activated, disrupting the cells’ metabolic and epigenetic stability. Using single-cell transcriptomics and stringent functional assays, the researchers found that suppressing this hyperactivation with a specific vacuolar ATPase inhibitor restored lysosomal integrity and blood-forming stem cell function.

The old stem cells started acting young and healthy once more. Old stem cells regained their regenerative potential and ability to be transplanted and to produce more healthy stem cells and blood that is balanced in immune cells; they renewed their metabolism and mitochondrial function, improved their epigenome, reduced their inflammation, and stopped sending out “inflammation” signals that can cause damage in the body.

Remarkably, ex vivo treatment (when cells are removed from the body, modified in a laboratory, and returned to the body) of old stem cells with the lysosomal inhibitor boosted their in vivo blood-forming capacity more than eightfold, demonstrating that correcting lysosomal dysfunction can restore regenerative potential.

This restoration also dampened harmful inflammatory and interferon-driven pathways by improving lysosomal processing of mitochondrial DNA and reducing activation of the cGAS-STING immune signaling pathway, which they find to be a key driver of inflammation and aging of stem cells.

Researchers have discovered how to reverse aging in blood-forming stem cells in mice by correcting defects in the stem cell’s lysosomes. The breakthrough, published in Cell Stem Cell, identifies lysosomal hyperactivation and dysfunction as key drivers of stem cell aging and shows that restoring lysosomal slow degradation can revitalize aged stem cells and enhance their regenerative capacity.

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Video NeuroImage: Stereotypic Motor Behaviors in a Patient With Pantothenate Kinase–Associated Neurodegeneration

A 24-year-old woman with pantothenate kinase–associated neurodegeneration (PKAN) presented with a 5-year history of psychiatric symptoms followed by prominent stereotypic motor behaviors, including repetitive touching of her mouth and leg, object manipulation, and tip-toe walking (Video 1). Examination revealed severe depression and anxiety, mild speech dysfluency, and the stereotypic movements. Previous symptomatic treatments provided limited benefit. Brain magnetic resonance imaging demonstrated the pathognomonic “eye-of-the-tiger” sign, indicative of iron deposition in the bilateral globus pallidus (Figure). Genetic testing identified compound heterozygous variants in the PANK2 gene: a known pathogenic variant (c.401AG) and a novel likely pathogenic variant (c.1465CG).

ANK3 as a Novel Genetic Biomarker for Liafensine in Treatment-Resistant Depression: The ENLIGHTEN Randomized Clinical Trial

Liafensine was efficacious and well tolerated in ANK3-positive patients with treatment-resistant depression, with clinically meaningful and statistically significant improvements over placebo, highlighting ANK3 as a predictive genetic biomarker for liafensine.

Question Does the newly discovered ANK3 pharmacogenomic biomarker predict the response of patients with treatment-resistant depression (TRD) to liafensine, a triple reuptake inhibitor, despite failure in a non–biomarker-selected TRD patient population in prior phase 2b trials?

Findings In this randomized clinical trial including 189 ANK3-positive patients with TRD, liafensine demonstrated a 4.4-point Montgomery-Åsberg Depression Rating Scale improvement over placebo, a clinically meaningful and statistically significant difference.

Meaning This represents a first successful genetic biomarker-guided clinical trial in psychiatry, advancing a new treatment for TRD and providing a new path for developing precision medicines in the field.

Novel Gene Therapy Treats T Cell Leukemia

Scientists at the University College London (UCL) have developed a novel therapy that helps treat patients with T cell acute lymphoblastic leukemia (T-ALL). This form of therapy used genome editing tools to modify immune cells and boost immune system response. T-ALL is a rare and aggressive blood cancer that affects specialized immune cells, known as T cells. This immune subset is responsible for identifying and targeting foreign pathogens. Unfortunately, in T-ALL, genetic mutations prevent T cells from maturing and properly functioning.

The world’s first gene therapy (BE-CAR7) uses base-editing, which can specifically change a single base in a cell’s DNA. BE-CAR7 was the first therapy to treat T-ALL in both children and adults. In 2022, a 13-year old girl was given BE-CAR7 followed by another eight children and two adults undergoing the same treatment. The following results from these patients were published in the New England Journal of Medicine (NEJM), by Dr. Waseem Qasim and others. Qasim is a Professor of Cell and Gene Therapy in the Department of Infection, Immunity, and Inflammation at the UCL. His work focuses on pediatric oncology with a focus in gene therapy. Qasim’s work has long involved treatment of T-ALL and improving therapies for children with leukemia.

Qasim and his team reported that 82% of patients receiving BE-CAR7 achieved remission, which allowed them to undergo stem cell transplant without disease. Treatment was accompanied by tolerable side effects, including low blood counts, cytokine release syndrome, and rashes. Additionally, 64% of patients remained disease-free even after three years. These remarkable results indicate the strong impact gene therapy has on T-ALL.

Dr. Norman Putzki, MD — Novartis — Gene Therapy And A New Era Of Neuroscience

Gene Therapy And A New Era Of Neuroscience — Dr. Norman Putzki, MD — SVP, Global Clinical Development Head, and U.S. Development Site Head, Novartis.

Dr. Norman Putzki, MD is Senior Vice President, Global Clinical Development Head, and U.S. Development Site Head at Novartis (https://www.novartis.com/) where he oversees global teams working on next-generation gene therapies, RNA-based medicines, targeted biologics, and innovative small molecules.

Dr. Putzki most recently served as Global Head of Development for Neuroscience and Gene Therapy at Novartis, where he oversaw one of the world’s most ambitious pipelines aimed at transforming the lives of patients with neurological, neuromuscular, and rare genetic diseases.

A physician–scientist by training, with an MD from University of Duisburg Essen, Dr. Putzki has built a career at the intersection of clinical medicine, translational research, and large-scale drug development.

Before joining Novartis, Dr. Putzki led programs across multiple therapeutic areas at Biogen Idec and has played key roles in advancing clinical treatments for conditions long considered intractable including MS and Parkison’s disease.

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Safe and effective in vivo delivery of DNA and RNA using proteolipid vehicles

Current genetic medicines are limited by tolerability, scalability, and immunogenicity issues. Utilizing components from viral and non-viral delivery platforms, we developed a lipid-based delivery vehicle formulated with a chimeric fusion protein that delivers nucleic acid cargo inside cells effectively and with broad distribution and low immunogenicity. This proteolipid vehicle platform is suitable for safe and effective repeat dosing of DNA and/or RNA in vivo.

From mind-controlling tech to clinical therapy

Researchers at the University of Geneva, together with colleagues in Switzerland, France, the United States and Israel, describe how optogenetic control of brain cells and circuits is already steering both indirect neuromodulatory therapies and first-in-human retinal interventions for blindness, while sketching the practical and ethical conditions needed for wider clinical use.

Optogenetic control uses light to impose temporally precise gain or loss of function in specific cell types, or even individual cells. Selected by location, connections, gene expression or combinations of these features, researchers now have an unprecedented way to investigate the brain within living animals.

Modern experiments range from implanted fiber optics to three-dimensional holographic illumination of defined neuronal ensembles and noninvasive wearable LEDs, with interventions that can run from milliseconds to chronic use and effect sizes that change rapidly with changes in light intensity.

Molecular basis for de novo thymus regeneration in a vertebrate, the axolotl

In humans, the loss of thymic function through thymectomy, environmental challenges, or age-dependent involution is associated with increased mortality, inflammaging, and higher risk of cancer and autoimmune disease (1). This is largely due to a decline in the intrathymic naïve T cell pool, whose generation is orchestrated by the thymic stroma, particularly thymic epithelial cells (TECs) (2). Upon challenges that affect the TEC compartment, the thymus is capable of triggering an endogenous regenerative response by engaging resident epithelial progenitors with stem cell features (3–5). Yet, after age-related atrophy or thymectomy resulting from myasthenia gravis or tumor removal (1), this regenerative response is unable to overcome the loss of thymic tissue, highlighting the need for therapeutic interventions.

The restoration of thymic functionality has been achieved to a limited extent via strategies targeting the thymic epithelial microenvironment or hematopoietic progenitors, modulating hormones and metabolism, or through cellular therapies and bioengineering (6). In mice, the up-regulation of Foxn1, a key transcription factor for thymus development and organogenesis (7), either directly or via its upstream effector bone morphogenetic protein 4 (BMP4), can support activity of cortical TECs (cTECs) (8, 9). Further, a combination of growth hormone and metformin has been shown to restore thymic functional mass in humans (10). Nevertheless, such strategies only lead to delayed thymic involution, and examples of complete thymus regeneration have not yet been described among vertebrates.

Because of its remarkable regenerative abilities that extend to parts of the brain, eye, heart, and spinal cord, and even entire limbs, the axolotl (Ambystoma mexicanum) is a powerful model for regeneration studies (11). The axolotl has offered insights into the mechanisms of positional identity (12), cell plasticity (13, 14), and the molecular basis of complex regeneration (15–18). The regeneration of axolotl body parts relies on remnants of the missing structure, with the exception of lens tissue, which can regrow from dorsal pigmented epithelial cells during a short window during development (19). However, whether de novo regeneration can occur for an entire complex organ, in axolotls or any other vertebrate, is unknown.

Cell-Based Neurodegenerative Disease Modeling

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive upper and lower motor neuron (MN) degeneration with unclear pathology. The worldwide prevalence of ALS is approximately 4.42 per 100,000 populations, and death occurs within 3–5 years after diagnosis. However, no effective therapeutic modality for ALS is currently available. In recent years, cellular therapy has shown considerable therapeutic potential because it exerts immunomodulatory effects and protects the MN circuit. However, the safety and efficacy of cellular therapy in ALS are still under debate. In this review, we summarize the current progress in cellular therapy for ALS. The underlying mechanism, current clinical trials, and the pros and cons of cellular therapy using different types of cell are discussed. In addition, clinical studies of mesenchymal stem cells (MSCs) in ALS are highlighted. The summarized findings of this review can facilitate the future clinical application of precision medicine using cellular therapy in ALS.

ALS is believed to result from a combination of genetic and environmental factors (Masrori and Van Damme 2020). ALS exists in two forms: familial ALS (fALS) and sporadic ALS (sALS). fALS exhibits a Mendelian pattern of inheritance and accounts for 5–10% of all cases. The remaining 90–95% of cases that do not have an apparent genetic link are classified as sALS (Kiernan et al., 2011). At the genetic level, more than 20 genes have been identified. Among them, chromosome 9 open reading frame 72 (C9ORF72), fused in sarcoma (FUS), TAR DNA binding protein (TARDBP), and superoxide dismutase 1 (SOD1) genes have been identified as the most common causative genes (Riancho et al., 2019). Beyond genetic factors, the diverse pathological mechanisms of ALS-associated neurodegeneration have been discussed (van Es et al., 2017). The clinical symptoms of ALS are heterogeneous, with main symptoms including limb weakness, muscle atrophy, and fasciculations involving both upper and lower MNs.

‘Three-hit model’ involving genes and environment describes possible causes of autism

A new University of California San Diego School of Medicine study offers a unified biological model to explain how genetic predispositions and environmental exposures converge to cause autism spectrum disorder (ASD).

The study, published in Mitochondrion, describes a “three-hit” metabolic signaling model that reframes autism as a treatable disorder of cellular communication and energy metabolism. The model also suggests that as many as half of all autism cases might be prevented or reduced with prenatal and early-life interventions.

“Our findings suggest that autism is not the inevitable result of any one gene or exposure, but the outcome of a series of biological interactions, many of which can be modified,” said study author Robert K. Naviaux, M.D., Ph.D., professor of medicine, pediatrics and pathology at UC San Diego School of Medicine.

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